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White adipose tissue (WAT) fibrosis is a hallmark of dysfunctional WAT that is directly linked to metabolic abnormalities. Recent studies have highlighted the role of dysfunctional adipose progenitor cells (APCs) in WAT fibrosis and impaired adaptive tissue plasticity, leading to systemic insulin resistance. However, therapeutic options for WAT fibrosis are limited. Intermittent fasting (IF) is an effective dietary regimen for weight control and metabolic improvement through various mechanisms, including healthy remodeling of WAT. However, whether IF is effective in improving age-associated WAT fibrosis and metabolic homeostasis is unknown. Here, we show that IF confers therapeutic benefits in aged and obese mice through reduction of WAT fibrosis. Single-cell analyses revealed that IF significantly reduces pro-fibrotic signatures within APCs along with upregulation of the circadian pathways, suggesting that the circadian clock of APCs mediates IF-induced WAT remodeling. Importantly, mice lacking core circadian gene exhibited increased fibrotic signatures in WAT and diminished beneficial response to IF, further supporting the importance of circadian rhythm in IF-mediated metabolic benefits. Lastly, insulin resistance in humans also presented with dysregulated circadian rhythm signatures in APC populations. Collectively, our findings highlight the novel role of the APC circadian rhythm in plasticity of WAT and metabolic response to IF.

In healthy blood vessels, albumin crosses the endothelium to leave the circulation by transcytosis. However, little is known about the regulation of albumin transcytosis or how it differs in different tissues; its physiological purpose is also unclear. Using total internal reflection fluorescence microscopy, we quantified transcytosis of albumin across primary human microvascular endothelial cells from both lung and skin. We then validated our in vitro findings using a tissue-specific knockout mouse model. We observed that albumin transcytosis was saturable in the skin but not the lung microvascular endothelial cells, implicating a receptor-mediated process. We identified the scavenger receptor CD36 as being both necessary and sufficient for albumin transcytosis across dermal microvascular endothelium, in contrast to the lung where macropinocytosis dominated. Mutations in the apical helical bundle of CD36 prevented albumin internalization by cells. Mice deficient in CD36 specifically in endothelial cells exhibited lower basal permeability to albumin and less basal tissue edema in the skin but not in the lung. Finally, these mice also exhibited a smaller subcutaneous fat layer despite having identical total body weights and circulating fatty acid levels as wild-type animals. In conclusion, CD36 mediates albumin transcytosis in the skin but not the lung. Albumin transcytosis may serve to regulate fatty acid delivery from the circulation to tissues.

Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders.

Identification of potent agonists of odorant receptors (ORs), a major class of G protein-coupled receptors, remains challenging due to complex receptor–ligand interactions. ORs are present in both olfactory and non-chemosensory tissues, indicating roles beyond odor detection that may include modulating physiological functions in non-olfactory tissues. Selective and potent agonists specific for particular ORs can be used to investigate physiological functions of ORs in non-chemosensory tissues. In this study, we designed and synthesized novel synthetic dehydroacetic acid analogues as agonists of odorant receptor 895 (Olfr895) expressed in bladder. Among the synthesized analogues, (E)-3-((E)-1-hydroxy-3-(piperidin-1-yl)allylidene)-6-methyl-2H-pyran-2,4(3H)-dione (10) exhibited extremely high agonistic activity for Olfr895 in Dual-Glo luciferase reporter (EC50=9 nm), Ca2+ imaging, and chemotactic migration assays. Molecular docking and site-directed mutagenesis studies suggested that a combination of hydrophilic and hydrophobic interactions is central to the selective and specific binding of 10 to Olfr895. The design of agonists armed with both hydrophilic and hydrophobic portions could therefore lead to highly potent and selective ligands for ectopic ORs.

Intermittent fasting (IF) is an effective dietary intervention to counteract obesity-associated metabolic abnormalities. Previously, we and others have highlighted white adipose tissue (WAT) browning as the main underlying mechanism of IF-mediated metabolic benefits. However, whether IF retains its efficacy in different models, such as genetically obese/diabetic animals, is unknown. Here, leptin-deficient ob/ob mice were subjected to 16 weeks of isocaloric IF, and comprehensive metabolic phenotyping was conducted to assess the metabolic effects of IF. Unlike our previous study, isocaloric IF-subjected ob/ob animals failed to exhibit reduced body weight gain, lower fat mass, or decreased liver lipid accumulation. Moreover, isocaloric IF did not result in increased thermogenesis nor induce WAT browning in ob/ob mice. These findings indicate that isocaloric IF may not be an effective approach for regulating body weight in ob/ob animals, posing the possible limitations of IF to treat obesity. However, despite the lack of improvement in insulin sensitivity, isocaloric IF-subjected ob/ob animals displayed improved glucose tolerance as well as higher postprandial insulin level, with elevated incretin expression, suggesting that isocaloric IF is effective in improving nutrient-stimulated insulin secretion. Together, this study uncovers the insulinotropic effect of isocaloric IF, independent of adipose thermogenesis, which is potentially complementary for the treatment of type 2 diabetes.

Alcoholic liver disease (ALD) is a worldwide health problem and hepatocyte apoptosis has been associated with the development/progression of ALD. However, no definite effective pharmacotherapy for ALD is currently available. Cilostazol, a selective type III phosphodiesterase inhibitor has been shown to protect hepatocytes from ethanol-induced apoptosis. In the present study, the underlying mechanisms for the protective effects of cilostazol were examined. Primary rat hepatocytes were treated with ethanol in the presence or absence of cilostazol. Cell viability and intracellular cAMP were measured. Apoptosis was detected by Hoechst staining, TUNEL assay, and caspase-3 activity assay. The roles of cAMP and AMP-activated protein kinase (AMPK) pathways in the action of CTZ were explored using pharmacological inhibitors and siRNAs. Liver from mice received ethanol (5 g/kg body weight) by oral gavage following cilostazol treatment intraperitoneally was obtained for measurement of apoptosis and activation of AMPK pathway. Cilostazol inhibited ethanol-induced hepatocyte apoptosis and potentiated the increases in cAMP level induced by forskolin. However, the anti-apoptotic effect of cilostazol was not reversed by an inhibitor of adenylyl cyclase. Interestingly, cilostazol activated AMPK and increased the level of LC3-II, a marker of autophagy. The inhibition of AMPK abolished the effects of cilostazol on LC3-II expression and apoptosis. Moreover, the inhibition of LKB1 and CaMKK2, upstream kinases of AMPK, dampened cilostazol-inhibited apoptosis as well as AMPK activation. In conclusion, cilostazol protected hepatocytes from apoptosis induced by ethanol mainly via AMPK pathway which is regulated by both LKB1 and CaMKK2. Our results suggest that cilostazol may have potential as a promising therapeutic drug for treatment of ALD.

Oilseed rape (Brassica napus L.) is an important crop due to its high oil content in the seed. Recently, the demand for the improvement of crop for biodisel energy source is increased as oil prices in the world has increased dramatically. Until now, oilseed rape breeding was carried out by cross-hybridization between different varieties and related germplasms. However, like as many other crops, the application of tissue culture and gene transformation systems has been introduced into oilseed rape breeding program including the development of transgenic canola plants. In this study, we reviewed a history of tissue culture and genetic transformation research in oilseed rape plants and indicated some important aspects for the production of transgenic oilseed rape plants.

Fat accumulation in the liver involves an imbalance in the hepatic uptake of free fatty acids and their metabolism. Fat accumulation in the liver plays a critical role in the initiation of nonalcoholic steatohepatitis, which may progress to liver fibrosis and cirrhosis. The prevention of hepatic fat accumulation, therefore, may be effective therapy for nonalcoholic fatty liver disease. However, the effect of insulin sensitizing drugs on hepatic fat accumulation is still unclear. Here, we show that metformin, the most widely used insulin sensitizer, prevents liver fat accumulation induced by a high-fat diet. Male C57BL/6 mice weighing 18°20 g were grouped as follows for 8 weeks: mice chow diet, high-fat diet pair-fed control, and high-fat diet with metformin. Triglyceride and total cholesterol levels in plasma and liver were measured. AMP-activated protein kinase activity in liver were determined by Western blot. Expressions of SREBP1c and FAS in the liver were measured using RT-PCR. The high-fat diet increased body weight, abdominal fat mass, fat accumulation in the liver, and plasma total cholesterol, as well as liver triglyceride and total cholesterol levels, but plasma triglyceride levels were unchanged. Metformin decreased each of these measures. The high-fat diet decreased liver AMP-activated protein kinase activity as well as SREBP-1c and FAS expressions, and metformin reversed these changes. In conclusion, a high-fat diet induced visceral obesity and hepatic fat accumulation. Metformin prevented visceral obesity, hepatic fat accumulation, and reduced plasma total and LDL-cholesterol concentrations, potentially through modulating AMP-activated protein kinase activity and the expressions of SREBP-1C and FAS.

Atopic dermatitis (AD) is a familial and chronic inflammatory pruritic skin disease that affects a large number of children and adults in industrialized countries. It is known that one of the prominent features of AD and chronic pruritus is partially due to the histamine released from mast cell. In this work, hydrogel patches with natural herbal extracts were prepared by “freezing and thawing”, and a gamma irradiation. It showed eminent healing results as a consequence of long-term moisturizing effects and natural herbal extracts on atopic wounds. Besides its non-toxicity and human harmlessness, it can be easily attached to or detached from the skin without any trace and help patients to feel refreshment when attached. Based on this work, the hydrogel patches we made can be potentially used as an alternative remedy for not only pruritus in AD, but other dermatitis.

A silver nanoparticle (AgNPs) stabilizer, polyvinyl alcohol (PVA) generally contains a relatively large amount of sodium acetate (NaOAc) as an impurity (up to several weight percentages) as a result of a base-catalyzed hydrolysis of poly(vinyl acetate) (PVAc). In this study, the effects of NaOAc on the radiolytic formation of AgNPs in PVA solutions were studied by using UV/vis spectroscopy. Several AgNPs were prepared by γ -ray irradiation using 60 Co source at various doses in the presence of various amounts of NaOAc. The UV data of the AgNPs observed at around 410 nm show that more AgNPs are generally produced as the NaOAc concentration in the PVA solution increases. Furthermore, no significant absorption band of the AgNPs was observed when the purified PVA containing a very small amount of NaOAc (less than 3×10 −4 M) was applied with 1×10 −3 M AgNO 3 up to 10 kGy. These results reveal that NaOAc present as an impurity in PVA, plays an important role in the radiolytic formation of AgNPs.

Most high-affinity phosphate transporter genes (OsPTs) in rice were highly induced in roots when phosphate was depleted. OsPT1, however, was highly expressed in primary roots and leaves regardless of external phosphate concentrations. This finding was confirmed histochemically using transgenic rice plants that express the GUS reporter gene under the control of the OsPT1 promoter, which exhibited high GUS activity even in the phosphate sufficient condition. Furthermore, transgenic rice plants overexpressing the OsPT1 gene accumulated almost twice as much phosphate in the shoots as did wild-type plants. As a result, transgenic plants had more tillers than did wild-type plants, which is a typical physiological indicator for phosphate status in rice.

Phosphate, a favorable phosphorous form for plant, is one of major nutrient elements for growth and development in plants. Plants exhibit various physiological and biochemical responses in reaction to phosphate starvation in order to maintain phosphate homeostasis. Of them, expression of high affinity phosphate transporter gene family and efficient uptake of phosphate via them is a major physiological process for adaption to phosphate deficient environment. Although the various genetic resources of high affinity phosphate transporter are identified recently, little is known about their functions in plant that is prerequisite information before applying to crop plants to generate valuable transgenic plants. We demonstrated that Arabidopsis transgenic plants over-expressing two different high affinity phosphate transporter gens, OsPT1 and OsPT7, derived from rice, exhibit better growth responses compared with wild-type under phosphate starvation condition. Specially, OsPT7 gene has proven to be more effective to generate Arabidopsis transgenic plant tolerant to phosphate deficiency than OsPT1. Furthermore, the expression level of AtPT1 gene that is one of reporter genes specifically induced by phosphate starvation was significantly low compared with wild-type during phosphate starvation. Taken together, these results collectively suggest that over expression of OsPTl and OsPT7 genes derived from monocotyledonous plant function efficiently in the dicotyledonous plant, relieving stress response caused by phosphate starvation and leading to better growth rate.

Cell surface biomarkers such as prostate-specific membrane antigen (PSMA) and hepsin have received considerable attention as targets for imaging prostate cancer (PCa) due to their high cell surface expression in such tumors and easy access for imaging probes. Novel amidine-containing indole analogs (13–21) as hepsin inhibitors were designed and synthesized. These compounds showed in vitro inhibitory activity against hepsin with IC50 values from 5.9 to 70 μM. Based on the SAR of amidine-derived analogs, the novel heterobivalent compound 30, targeting both hepsin and PSMA, was synthesized by linking compound 18 with Lys-urea-Glu, the key scaffold for the specific binding to PSMA, followed by the conjugation of the optical dye SulfoCy7. Compound 30 exhibited inhibitory activities against PSMA and hepsin, with IC50 values of 28 nM and 2.8 μM, respectively. In vitro cell uptake and preliminary in vivo optical imaging studies of 30 showed selective binding and retention in both PSMA and hepsin high-expressing PC3/ML-PSMA-HPN cells as compared with low-expressing PC3/ML cells.

Biofilm formation on biotic or abiotic surfaces has unwanted consequences in medical, clinical and industrial settings. Treatments with antibiotics or biocides are often ineffective in eradicating biofilms. Promising alternatives to conventional agents are biofilm-inhibiting compounds regulating biofilm development without toxicity to growth. Here, we screened a biofilm inhibitor, raffinose, derived from ginger. Raffinose, a galactotrisaccharide, showed efficient biofilm inhibition of Pseudomonas aeruginosa without impairing its growth. Raffinose also affected various phenotypes such as colony morphology, matrix formation and swarming motility. Binding of raffinose to a carbohydrate-binding protein called LecA was the cause of biofilm inhibition and altered phenotypes. Furthermore, raffinose reduced the concentration of the second messenger, cyclic diguanylate (c-di-GMP), by increased activity of a c-di-GMP specific phosphodiesterase. The ability of raffinose to inhibit P. aeruginosa biofilm formation and its molecular mechanism opens new possibilities for pharmacological and industrial applications.

A major impurity in poly (vinyl alcohol) (PVA) is sodium acetate which remains after its preparation by a base catalyzed hydrolysis of poly(vinyl acetate), and the amount of sodium acetate in commercial PVA samples may reach several percentages. To establish an optimal condition for the removal of sodium acetate, several washing parameters such as washing period, solvent polarity, and temperature were investigated in this study. Nuclear magnetic resonance (NMR) spectroscopy was successfully applied to determine the residual amounts of sodium acetate in the purified poly(vinyl alcohol). The relative integral value for the methyl peak of sodium acetate in PVA was converted to a relative mass value and finally to the sodium acetate content contained in PVA. The results showed that over 95% of sodium acetate in PVA was removed by a washing of PVA with distilled water within 2 h. When methanol was used as a washing solvent, a higher temperature than room temperature was required for an effective removal of sodium acetate. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

Background and purpose In many cardioembolic strokes (CSs), the specific embolic source is uncertain. Despite the high mortality of CS, not enough attention is paid to its potential source. Although atrial fibrillation (AF) is the most common source of embolism, more complex and dynamic multiplicities may influence CS. The aim of this study was to evaluate novel indicators of transthoracic echocardiography (TTE) that have additional value for detecting CS. Methods In total, 1878 patients with acute ischaemic stroke who had TTE during admission were identified. Of the patients with undetermined etiology, 93 patients with incomplete evaluations were excluded. Thereafter, two stroke neurologists reviewed all of the magnetic resonance images to assess cardioembolic lesion patterns. The patients were classified into two groups: potential cardioembolic stroke (PCS) and non-PCS. Results Amongst a total of 1601 patients, 518 (32.4%) had PCS. About half of the patients with PCS had AF. Patients with PCS were more likely to have larger left ventricular (LV) end-diastolic diameters, larger LV end-systolic diameters, larger left atrial sizes, increased E/A ratios and reduced LV ejection fractions. After adjusting for multiple clinical and TTE variables including AF, an E/A ratio ≥1.5 had a significant predictive value for PCS (odds ratio 2.89, 95% confidence interval 1.57–5.31, P

1-Methyl-3-(1,1,3-trioxo-1,3-dihydro-1λ-benzo[d]isothiazol-2-ylmethyl)-imidazolidine-2,4,5-triones 5a, 1-ethy1-3-(1,1,3-trioxo-1,3-dihydro-lλ/-benzo[d]isothiazol-2-ylmethyl)-imidazolidine-2,4,5-triones 5b 1-phenyl-3-(1,1,3-trioxo-1,3-dihydro-1λ-benzo [d]isothiazol-2-ylmethyl)-imidazolidine-2,4,5-triones 5c were obtained by means of 4 reaction steps involved the reaction of 1-methyl-urea and oxalyl chloride. Biological tests(Plant Response Screening Result, Insect Primary Screening Result and Fungicide Primary Screening Result) of synthesized sacccarin derivatives were executed.

Purpose: Dysregulation of adipokines caused by excess adipose tissue has been implicated in the development of obesity-related metabolic diseases. This study evaluated the effects of mugwort (Artemisia princeps Pampanini) ethanol extract on lipid metabolic changes, insulin resistance, adipokine balance, and body fat reduction in obese rats. Methods: Male Sprague-Dawley rats were fed either a control diet (NC), high-fat diet (HF, 40% kcal from fat), or high-fat diet with 1% mugwort extract (HFM) for 6 weeks. Results: Epididymal and retroperitoneal fat mass increased in the HF group compared with the NC group, and epididymal fat mass was reduced in the HFM group (p < 0.05). No difference was observed in serum levels of total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) among the groups. However, triglyceride (TG), TG/HDL-C ratio, and TC/HDL-C ratio increased in the HF group and significantly decreased in the HFM group. TG and TC levels in the liver were significantly higher in the HF group, whereas these levels were significantly reduced in the HFM group. HF rats had lower insulin sensitivity as indicated by increased homeostasis model assessment of the insulin resistance (HOMA-IR) value. HOMA-IR values significantly decreased in the HFM group. Adiponectin levels were higher in NC rats, and their leptin and PAI-1 levels were lower. Relative balance of adipokines was reversed in the HF group, with lower adiponectin levels but higher leptin and PAI-1 levels. In contrast, the HFM group maintained balance of adiponectin/leptin and adiponectin/PAI-1 levels similar to NC by reducing leptin and PAI-1 levels. Conclusion: Overall data indicated that mugwort extract can be effective in alleviating metabolic dislipidemia, insulin resistance, and adipokine dysregulation induced by a high-fat diet.

Endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and mitochondrial biogenesis were assessed following varying intensities of exercise training. The animals were randomly assigned to receive either low- (LIT, n=7) or high intensity training (HIT, n=7), or were assigned to a control group (n=7). Over 5 weeks, the animals in the LIT were exercised on a treadmill with a 10° incline for 60 min at a speed of 20 m/min group, and in the HIT group at a speed of 34 m/min for 5 days a week. No statistically significant differences were found in the body weight, plasma triglyceride, and total cholesterol levels across the three groups, but fasting glucose and insulin levels were significantly lower in the exercise-trained groups. Additionally, no statistically significant differences were observed in the levels of PERK phosphorylation in skeletal muscles between the three groups. However, compared to the control and LIT groups, the level of BiP was lower in the HIT group. Compared to the control group, the levels of ATF4 in skeletal muscles and CHOP were significantly lower in the HIT group. The HIT group also showed increased PGC-1α mRNA expression in comparison with the control group. Furthermore, both of the trained groups showed higher levels of mitochondrial UCP3 than the control group. In summary, we found that a 5-week high-intensity exercise training routine resulted in increased mitochondrial biogenesis and decreased ER stress and apoptotic signaling in the skeletal muscle tissue of rats.